An urgent need exists to develop novel therapies for cardiac failure. The Na+/K+ ATPase (NKA) catalyzes active transport of Na+ and K+ ions across the cardiomyocyte plasma membrane. Cardiac glycosides are thought to have a positive inotropic effect by inhibiting NKA. Recent work of Xu et al. (2005, 2006) identified an activation site on NKA. An affinity purified antiserum specific for this extracellular site markedly augments NKA catalytic activity both in vitro and in vivo in rodents. The augmented NKA activity is correlated with a positive inotropic action in vivo. Spontaneously hypertensive rats (SHHF) develop a severe, lethal hypertensive cardiomyopathy. High titer anti-NKA antibodies elicited in SHHF by active immunization completely prevented the lethal CHF of these animals with no noticeable adverse effects over a period of 30 weeks. Based on these initial proof-of principle studies, we have identified several high affinity anti-NKA Fabs from our human Fab phagemid library. The overall goal of phase I will be to characterize a panel of NKA- specific human monoclonal antibodies. The panel will be rank-ordered based on NKA-activating activities in vitro and in vivo. The best "Inotropic Humab" will be selected for preclinical pharmtox and further animal studies to be carried out in Phase II. The preliminary studies of Xu et al., using the rabbit antiserum and active immunization using an NKA-specific peptide, suggest that this approach will provide a novel immunotherapeutic for heart failure. PUBLIC HEALTH RELEVANCE: Narrative: An urgent need exists to develop novel therapies for cardiac failure. We have developed antibodies that may both enhance survival and the qualtiy of life for heart failure patients by increasing the strength of the heart's contractions.